Method for determining concentration; a dialyser

ABSTRACT

The present invention relates to a method for determining the concentration of an ion, atom or molecule bound in a complex. A reliable determination of the concentration of the ion, atom or molecule to be determined is possible in accordance with the invention in that the complexing of the ion, atom or molecule is prevented at least during the determination of the concentration by the addition or withdrawal of a substance. The present intervention further relates to a dialyser having a haemo-dialyser and/or a haemo-filter and having an extra-corporal blood circulation with which means for the adding of citrate to the blood are connected upstream of the haemo-dialyser and/or of the haemo-filter and means for the adding of a substitution solution containing ions to the blood are connected downstream of the haemo-dialyser and/or of the haemo-filter, and having a dialysate line which has means for the detection of an ion concentration in the dialysate downstream of the haemo-dialyser and/or of the haemo-filter with respect to the direction of flow of the dialysate.

[0001] The present invention relates to a method for determining theconcentration of an ion, atom or molecule bound in a complex.

[0002] Numerous ions, atoms and molecules are not present in isolatedform, but in the form of the most different complexes. This relates toions, atoms and molecules both in the blood circulation of a patient andin the blood that is taken from the patient for the purpose of a certainblood treatment or patient treatment and has suitable complex agentsadded outside the body.

[0003] An example for the complexing of ions is so-called citrateanti-coagulated haemodialysis/haemofiltration. Here, a complexing ofCa⁺⁺ ions of the blood takes place in the extra-corporal bloodcirculation by means of citrate in order to inhibit blood clottingduring the treatment, above all during the blood/membrane contact in thedialyser.

[0004] Inhibition of blood clotting is required with most haemodialysispatients today. The standard is to use non-fractioned heparin that isinfused into the arterial side of the extra-corporal hose system by asyringe pump. The use of both non-fractioned heparin and alternativeanti-coagulants such as low-molecular-weight heparin or hirudin isproblematic for some of the patients and for other extra-corporal bloodtherapies for the following reasons:

[0005] Anti-coagulation has a systemic effect (that is not only onmembrane contact in the extra-corporal circulation, but in the wholebody), which results in critical haemorrhage risk for some patients. Inparticular in the intensive medical area, 30 to 40% of patients are atrisk of haemorrhage.

[0006] Some patients show incompatibility reactions such asheparin-induced thrombocytopenia which exclude the use of theseanti-coagulants.

[0007] Adsorptive therapies (for example liver replacement therapy) canbe incompatible with the use, for example, of heparin if thisneutralises the binding points of the adsorber (provided for theadsorption of toxins).

[0008] An alternative which avoids the problems listed is regionalclotting inhibition (only in the extra-corporal circulation, above allduring the blood/membrane contact) by citrate. In this method shown inFIG. 1, the concentration of free calcium (Ca) is reduced by so much bythe addition of tri-sodium citrate at the point in accordance with Pos.1 in FIG. 1 that the clotting cascade is interrupted, with two citratemolecules in case forming a complex with three Ca ions. The use ofCa-free dialysate in accordance with Pos. 2 in FIG. 1 and the Cawithdrawal this causes also contributes to the concentration reduction.To avoid depletion of the body with respect to Ca and Mg (which is alsobound by citrate), a further solution (see Pos. 3 in FIG. 1) containingCa ions and Mg ions in an adapted concentration must be infused into thevenous side of the extra-corporal circulation or into a separate venousentry.

[0009] Clinical studies [Morita Y, Johnson R W, Doren R E, Hall D S,“Regional anticoagulation during hemodialysis using citrate”. TheAmerican Journal of the Medical Sciences (1961); Janssen M J M F et al.,“Citrate compared to low molecular weight heparin anticoagulation inchronic hemodialysis patients”, Kidney Int (1996) 49:806-813; Mehta R L,McDonald B R, Aguilar M M, Ward D M, “Regional citrate anticoagulationfor continuous arteriovenous hemodialysis in critically ill patients”,Kidney Int (1990) 38:976-981] demonstrate that regional citrateanti-coagulation very effectively prevents blood clotting in theextra-corporal circulation. At the same time, an increased risk ofhaemorrhage for the patient is avoided. Citrate dialysis is thereforeseen as an interesting, effective alternative to conventional heparinanti-coagulation for that part of the patient population in which—asdescribed above—the use of heparin is disadvantageous or clearlycontra-indicated.

[0010] Despite these clear therapeutic advantages, citrateanti-coagulation has only been used to a low extent up to now and not asan automated, standardised process. The reasons for this are:

[0011] 1. The increased effort: in conventional dialysis, standardhaemo-dialysis solution and a low amount of heparin is required. Incitrate dialysis, three solutions are usually required: thehaemo-dialysis solution free of Ca and Mg and adapted in the Na andbicarbonate content, the tri-sodium citrate solution and the Ca⁺⁺/Mg⁺⁺solution.

[0012] 2. Safety aspects in the dosing of the Ca⁺⁺/Mg⁺⁺ solution: if anincorrect dose is given here, a life-threatening situation can quicklyarise (tetany, cardiac irregularity, cardiac arrest). Incorrect dosingcan arise as a result of technical problems (e.g. failure of the pump,leaks, etc.), or by an incorrect determination of the Ca requirement.

[0013] 3. Consequences of a supply of citrate or of the Ca₃-Ci₂ orMg₃-Ci₂ complexes: metabolic alkalosis, non-physiological Caconcentration.

[0014] The increased effort of the process can be limited by a suitabletechnical realisation; certain additional costs are quite justified inpatients with heparin incompatibilities. The supply of citrate or ofcitrate complexes can be greatly reduced by efficient withdrawal via themembrane (use of a large-area high-flux filter, possibly in combinationwith post-dilution HDF). A low remaining supply can probably betolerated; if not, it can also be estimated and compensated by suitablemodelling of the dialysis process and of the metabolisation of thecomplexes.

[0015] A citrate anti-coagulated dialysis method is known from WO91/06326. Tri-sodium citrate is added to the arterial supply line of theextra-corporal blood circulation as the anti-coagulant, with the addedamount of tri-sodium citrate per time unit only being adapted to theblood stream rate in the extra-corporal circulation. If the blood streamrate increases or falls, the addition rate of tri-sodium citrate is alsoincreased or lowered respectively. The calcium ion concentration of thepatient blood is not monitored in a close-meshed manner here, butdetermined in fairly large time intervals by blood samples. Since aclose-meshed or continuous monitoring of the calcium concentration inthe blood of the patient is missing and since the amount of addedcitrate is oriented only on the blood flow rate and not on the calciumlevel of the patient, it cannot be reliably precluded in this previouslyknown method that calcium values result in the patient's blood which arenon-physiological and which can accordingly bring about life-threateningconsequences for the patient.

[0016] While ion-sensitive sensors are known by means of which thecalcium ion concentration or the magnesium ion concentration in theblood of a patient can also be determined in small time intervals, theuse of a sensor on the blood side is, however, disadvantageous andtherefore undesirable due to a possible toxicity, as a result ofsterility demands and for cost reasons.

[0017] It can also be necessary to make a concentration determination ofions, atoms or molecules bound in complexes in other applications thandialysis. Even under the assumption that ion-sensitive sensors could beused without disadvantages for the patient, their use in thedetermination of the concentration of complexed ions frequently does notdeliver any results, or any results which can be utilised, since theproperties of the ion present in the complex do not allow a meaningfulmeasurement.

[0018] It is therefore the object of the present invention to provide amethod for determining the concentration of an ion, atom or moleculebound in a complex by means of which the concentration of the ion, atomor molecule to be determined can be reliably found.

[0019] This object is solved by a method for determining theconcentration of an ion, atom or molecule bound in a complex in whichthe complexing of the ion, atom or molecule is prevented at least duringthe concentration determination by adding or withdrawing a substance.The present invention thus has the underlying idea for the purpose ofdetermining the concentration of avoiding the formation of the complexwith the ion, atom or molecule or of separating the ion, atom ormolecule from such a complex in order then to make the correspondingconcentration determination.

[0020] The added substance can be an acid. The complexing is in thiscase prevented by the change in pH associated with the addition of theacid, with the complexing agent being protonated and thus, as it were,deactivated for the complexing of the substance to be determined.

[0021] The complexing can be prevented in that the addition of thecomplexing agent is interrupted or the complexing agent enters into acomplex with another substance to be added and in this respect releasesthe ion, atom or molecule whose concentration is to be determined. Theaddition of a substance would thus be thinkable which has a higheraffinity to the complexing agent than the ion, atom or molecule to bedetermined. The latter are “separated” from the complex on the additionof this substance and are then available for a measurement.

[0022] In another aspect of the present invention, provision is madethat it is a method for determining the ion concentration of the bloodof a patient in citrate anti-coagulated haemo-dialysis and/orhaemo-filtration. In accordance with the invention, the ionconcentration of the blood is here determined on the basis of thedetermination of the ion concentration in the dialysate. Before the ionconcentration in the dialysate is determined, the complexing of therelevant ion is prevented by citrate for the purpose of determining theconcentration.

[0023] In this way, the ion concentration of the blood of a patient canbe monitored at a favourable cost and without safety risks for thepatient during the treatment.

[0024] Due to the fact that the determination of the ion concentrationdoes not take place in the blood of the patient, but in the dialysate,the substantial advantage results that sensors for measuring theblood/ion concentration and the above-mentioned disadvantages resultingtherefrom can accordingly be avoided. It is therefore not necessary tointerfere with the extra-corporal blood circulation in order todetermine the concentration. This applies correspondingly to therepeated taking of blood samples not required here.

[0025] In accordance with a preferred aspect of the present invention,the complexing is prevented in that the citrate addition into the bloodcirculation is temporarily interrupted. Since the concentration in thedialyser on the blood side does not correspond to the concentration inthe patient and since the ions, in particular the Ca ions and Mg ions,are bound to citrate by the complexing, the citrate infusion isinterrupted in accordance with this embodiment in order to also obtainthe actual ion concentration of Ca or Mg in the dialyser. Theinterruption of the citrate addition or of the citrate infusion can takeplace in regular intervals. The infusion of the Ca ions and Mg ions canbe maintained in these intervals since the ions released by theinterruption of the citrate addition are largely withdrawn from theblood in the dialyser. The infusion of the Ca ions and of the Mg ionscan also be reduced in order to just compensate the partial withdrawalin the dialyser. This monitoring method is discontinuous since thecitrate infusion can only be interrupted for short intervals in order toensure sufficient anti-coagulation. However, this is sufficient torecognise critical trends in time. In the event of under-dosing orover-dosing, or total failure of the Ca/Mg ion infusion, it namely takessome time until critical concentrations are reached in the body. Thistime lies at around ten minutes and depends above all on the blood flow.

[0026] In a further aspect of the present invention, provision is madethat the complexing is prevented in that the ion is released from theion/citrate complex in the dialysate by lowering the pH. Theconcentration of the ion released in this way is subsequentlydetermined. Such an embodiment of the present invention has theadvantage that an interruption of the citrate infusion is not necessaryhere. If the relevant ion, preferably Ca⁺⁺ and/or Mg⁺⁺, is released fromthe ion/citrate complex, the corresponding ion can be determined withoutproblem in the dialysate. The method is, however, relatively complexsince an additional infusion is necessary in order to effect therelease. Acid must be added on the dialysate side here. In addition, theion/citrate complex is relatively large with a molecular weight of 504(with Ca ions) so that a clearance is much lower than for electrolytes.The measurement or estimate of the blood side concentration from thedialysate concentration is then correspondingly more difficult. Whensetting a suitable pH, care is to be taken that the Ca ion or Mg ion isreleased as fully as possible since an only part release would result toblood concentration values which would be too low.

[0027] In another aspect of the present invention, provision is madethat after the interruption of the citrate addition, the measurement ofthe ion concentration in the dialysate is carried out at the end of alength of time which is composed of a dead time determined by deadvolumes and of a period of time required to achieve a quasi-stationarystate. The dead volume results from the volumes of the hose connectionbetween the infusion site for citrate and the cite of the measuringpoint for the corresponding ion concentration. Normally, dead times areto be expected in the range from around 10 to 30 s. The concentration onthe dialysate side increases thereafter. This increase is not abrupt,but time constants of around 1 to 2 min. are to be anticipated until aquasi-stationary state is achieved. A state is to be understood by thisfrom which changes in the concentrations are negligibly small or liewithin a pre-determined tolerance.

[0028] In accordance with a preferred aspect of the present invention,provision is made that after the interruption of the citrate addition,the measurement of the ion concentration in the dialysate is repeated amultiple of times and the measured value is determined on the reachingof a quasi-stationary state. The concentration in the dialysate is thusmeasured at a plurality of times, a concentration course is determinedin this way and it can then be evaluated whether the equilibriumconcentration is achieved with sufficient precision.

[0029] In another aspect of the present invention, provision is madethat after the interruption of the citrate addition, the measurement ofthe ion concentration in the dialysate is repeated a multiple of timesand the measured value is determined by extrapolation of the ionconcentration obtained in the dialysate. With this method, theequilibrium value is thus extrapolated from an increase behaviour of theconcentration in the dialysate measured over a sufficient interval oftime. This procedure has the advantage that it is not necessary to waitfor the equilibrium to be adopted. However, a knowledge of the timebehaviour of the concentration increase is required here.

[0030] In accordance with another preferred aspect, the citrateconcentration can be interrupted for a pre-determined time interval andthe measured value is determined by integration of the area of theresponse function defined by the ion concentration in the dialysate as afunction of time. The citrate infusion can be interrupted, for example,for a fixed, relatively short time interval, approximately 1 to 2 min. Aconclusion can then be made as to the equilibrium concentration byevaluation of the area under a pulse-like response function of theconcentration in the dialysate.

[0031] The measure of the intermittent interruption of the citrateinfusion naturally also interrupts the regional anti-coagulation in thedialyser. However, it cannot be anticipated that the a substantialimpairment of the anti-coagulation would result from this. For instance,in the so-called dialysis free of heparin, for example, which isactually a completely anti-coagulation-free dialysis with a cyclicrinsing of the extra-corporal circulation, the complication rate due toblood clotting is relatively low (less than 5%). It is therefore not tobe anticipated that an intermitting interruption of anti-coagulation,which could then amount in sum to a total of approximately 10 to 20% ofthe dialysis time, would result in clinical problems.

[0032] If complexing is prevented or opened in that the ion is releasedfrom the ion-citrate complex in the dialysate by lowering the pH, a pHof 2 to 3 is preferably set since here a correspondingly completedissociation of the complex can be realised.

[0033] The setting of a pH in the dialysate preferably takes place bymeans of an infusion of acid.

[0034] It is particularly advantageous if the dialysate flow is reducedfor the purpose of approximating the ion concentration of the dialysateto the ion concentration of the blood of the dialysate flow. The ionconcentration on the dialysate side is adapted to the ion concentrationon the blood side by a reduction of the dialysate flow.

[0035] It was shown theoretically and experimentally that when there isa reduction in the dialysate flow with an unchanging blood flow, theconcentration of low-molecular-weight substances approaches the bloodplasma concentration more and more. If the dialysate flow is selected tobe sufficiently low—dependent on the blood flow, the molecule inquestion and the dialyser used—the dialysate concentration ispractically identical to the blood concentration; the dialysate thenreaches saturation. In the case of ions, the dialysate concentrationwill, however, differ by some percent from the blood/plasmaconcentration in this state of the flow equilibrium due to the Donnaneffect, which can be taken into account mathematically with knowledge orestimation of the plasma protein content.

[0036] In another aspect of the present invention, provision is madethat the determination of the ion concentration of the blood takes placewithout a reduction in the dialysate flow by calculation. Such aprocedure has the advantage that the dialysate flow does not need to belowered and thus the dialysis efficiency is not reduced in this timeinterval.

[0037] Under normal treatment conditions, in which the dialysate flow islarger than or equal to the blood flow, a lower dialysate concentrationresults with respect to the blood concentration. With knowledge of thedialyser transport properties for the observed molecule/atom (k₀A), ofthe machine settings (blood and dialysate flow) and of the haematocrit,the blood plasma concentration can be calculated in a good approximationfrom the measured concentration on the dialysate side. With knowledge ofthe clearance, the concentration on the blood side is calculated fromthe simple formula

C _(Bi):=(Q _(D) /K)*C _(Do)

[0038] where C_(Bi) is the entry concentration on the blood side, C_(Do)is the measured exit concentration on the dialysate side, Q_(D) is thedialysate flow and K is the clearance. K is given for an in vitrosituation with a purely diffusing transfer by:$K:={Q_{B} \cdot \frac{{\exp \left\lbrack {{k0A} \cdot \left( {\frac{1}{Q_{B}} - \frac{1}{Q_{D}}} \right)} \right\rbrack} - 1}{{\exp \left\lbrack {{k0A} \cdot \left( {\frac{1}{Q_{B}} - \frac{1}{Q_{D}}} \right)} \right\rbrack} - \frac{Q_{B}}{Q_{D}}}}$

[0039] Corresponding, more complex formulae are also available for thein vivo situation, likewise for haemodialysis with ultra-filtration andfor filtration (HF) or combined filtration/diffusion (HDF) processes.This mathematical formula, which can be used for any desired dialysissituation, has been validated with in vitro and in vivo measurements andis available in a user-friendly form in the form of the software“Clearance Calculation Tool CCT” from FMC.

[0040] The possibility of reducing the dialysate flow is to be preferredwhen a precise measurement is required. However, it has the disadvantagethat the dialysate flow has to be lowered for some minutes and that thusthe dialysis efficiency is reduced correspondingly in this timeinterval. If, however, no very precise measurements are required for amonitoring of the Ca ion concentration, the method of calculating theion concentrations without lowering the dialysate flow can also be usedin which, accordingly, no influencing of the dialysis by the measuringmethod takes place, except for the intermittent interruption ofanti-coagulation.

[0041] It is particularly advantageous if the detection of the ionconcentration in the dialysate takes place by means of an ion-sensitivesensor in the dialysate flowing from the dialyser. The precision of thedetermination of the ion concentration of the blood is essentially givenby the sensor system. Since an incorrect display of the sensor incombination, for example, with an incorrect dosing represents a highpotential risk for the patient, the function of the sensor must beensured by a suitable test or by other measures. A repeated functiontest of the sensor during dialysis can be necessary, with the testintervals being able to be oriented on the time interval within which acritical state can develop for the patient (some 10 minutes).Alternatively, or additionally, redundant sensor systems can be used. Itis also possible to provide security systems which immediately detectand put on display a characteristic failure behaviour of the sensor.

[0042] In another aspect of the present invention, provision is madethat the determined ion concentration of the blood of a patient servesas a controlled variable whose value is influenced by the controlvariables of citrate addition and/or addition of a substitution mediumcontaining ions. A closed loop can thus be realised with a correspondingregulating unit here by which a desired value of the concentration of Caions and/or Mg ions can be set in the patient's blood. An independentlyoperating monitoring system for the haemo-dialysis and/orhaemo-filtration anti-coagulated by citrate can be realised in this wayby which a physiological value of the concentration of Ca ions and/or Mgions can always be set in the patient's blood. The citrate addition orthe addition of the corresponding substitution medium containing ionscan serve as the control variables. However, when selecting the citrateaddition as the control variable, it must be considered that these mustnot fall below certain limits in order to keep the ion concentrationslow in the region of the dialyser, which is necessary in order toeffectively avoid coagulation.

[0043] A particularly reliable embodiment of the following inventionresults from an alarm being triggered when the ion concentrationdetermined in the blood of the patient lies outside a permitted range ordiffers from a permitted value. An alarm can be triggered when anindividual measurement results in critically high or low values or whena critical trend is determined. Additionally or alternatively to analarm, suitable counter-measures can be initiated such as a bypassing ofthe machine, stopping of the infusions, changing of the infusion rates,etc.

[0044] In another aspect of the invention, provision is made that theion concentration in the compartment of the dialyser on the blood sideis determined without an interruption to the citrate supply and iscompared with a permitted threshold value and the citrate supply ischanged in dependence on this comparison. Such a procedure is meaningfulto check whether the citrate addition is sufficient to lower the Ca ionconcentration by so much that the coagulation risk is reduced to thedesired level. This naturally has to be determined with the citratesupply switched on since the excess free Ca has to be determined withcitrate supply. A regulating system is possible here which automaticallyvaries the citrate infusion rate in accordance with the measured Ca ionconcentration. The required Ca/Mg ion substitution can also bedetermined in this way.

[0045] As stated above, the ions are preferably calcium ions and/ormagnesium irons which are both bound in corresponding complexes bycitrate. The method is preferably carried out while determining the Caion concentration in the dialysate.

[0046] The present invention further relates to a dialyser having ahaemo-dialyser and/or a haemo-filter and having an extra-corporal bloodcirculation, with which means for the adding of citrate to the blood areconnected upstream of the haemo-dialyser and/or of the haemo-filter andmeans for the adding of a substitution solution containing ions to theblood are connected downstream of the haemo-dialyser and/or of thehaemo-filter, and having a dialysate line which has means to detect anion concentration in the dialysate downstream of the haemo-dialyserand/or of the haemo-filter with respect to the direction of flow. Themeans for detecting the ion concentration are preferably designed as oneor more ion-sensitive sensors. A redundant design increases theoperational reliability of the dialyser and allows the fast recognitionof incorrect measurements.

[0047] A reliable embodiment of the dialyser can be realised in that atest device is provided which makes a functional check of the sensor(s)in time intervals or on actuation by an operator.

[0048] Means can be in communication with the dialysis line for theaddition of a substance by which the pH of the dialysate can be changed.In this way, the ion to be determined can be determined by the pH changein its concentration after its release from the complex.

[0049] The means for the addition of the substance can be disposed suchthat the addition takes place downstream of the dialyser with respect tothe direction of flow of the dialysate.

[0050] In accordance with another aspect of the present invention, meansare provided by which the dialysate flow can be temporarily reduced. Theion concentration in the blood can be calculated particularly preciselyfrom the ion concentration in the dialysate by the reduction in thedialysate flow.

[0051] A control unit can be provided which controls the means for theaddition of citrate to the blood in time intervals or on actuation bythe operator such that the addition is temporarily interrupted and whichafter the start of the interruption of the citrate addition records theconcentration value determined by the means for detecting an ionconcentration in the dialysate continuously or in time intervals.

[0052] The control unit can be designed such that this determines themeasured value of the Ca⁺⁺ ion concentration in accordance with a methodin accordance with claims 7 to 10.

[0053] In accordance with another preferred design of the presentinvention, a regulating unit can be provided which is connected to theion-sensitive sensor and to the means for adding citrate and/or to themeans for adding a substitution solution containing ions and whichinitiates an increase or decrease in the addition amount of citrateand/or of substitution solution containing ions in dependence on thecomparison between a nominal value or a nominal value range and thedetermined actual value of the ion concentration. In this way, theconcentration in the blood of the patient can be regulated to a desiredvalue or in a desired interval.

[0054] The regulating unit and/or the means for the addition of citratecan be designed such that the concentration of citrate cannot be loweredbelow a threshold value. It is prevented in this way that the citrateconcentration does not fall below a certain value which is required forthe effective prevention of coagulation.

[0055] An alarm device can be provided which triggers an alarm ondetermination of a critical individual measurement of the ionconcentration or on determination of a critical trend of individualmeasurements. The operator's attention is thus drawn to such a criticalstate, for example acoustically and/or visually.

[0056] Further details and advantages of the present invention areexplained in more detail by means of an embodiment illustrated in thedrawing, There are shown:

[0057]FIG. 1: a schematic representation of a haemo-dialysis methodhaving citrate anti-coagulation with solutions used and the position ofthe supply;

[0058]FIG. 2: a schematic illustration in accordance with FIG. 1 with anadditional representation of a Ca ion sensor in the dialysate lineleading away from the dialyser;

[0059]FIG. 3: a representation of the adaptation of the concentration onthe dialysate side to the concentration on the blood side of an NaClsolution on reduction of the dialysate flow (in vitro experiment);

[0060]FIG. 4 a representation of the simulation of the concentrationdevelopment to be expected in the dialysate with an intermittentinterruption of the citrate infusion; and

[0061]FIG. 5 a schematic representation of a haemo-dialysis methodhaving anti-coagulation by citrate; determination of the Ca ionconcentration by dissociation of the Ca citrate complexes in thedialysate.

[0062]FIG. 1 shows a haemo-dialysis method with anti-coagulation bycitrate in a schematic representation. By the addition of tri-sodiumcitrate (see Pos. 1) in the part of the extra-corporal circulation whichleads from the patient to the dialyser, the concentration of free Caions is reduced by so much that the clotting cascade is interrupted. Atri-calcium bicitrate complex is created. A further reduction in theconcentration of Ca ions in the blood is caused in that dialysate freeof Ca (see Pos. 2) is used so that a correspondingly high gradient ofthe Ca ion concentration over the membrane results. In order to avoid anon-permitted depletion of calcium, and also magnesium which is alsobound by citrate, in the body of the patient, a substitution solution(see Pos. 3), which contains the Ca ions and Mg ions in an adaptedconcentration, is infused into the venous side of the extra-corporalcirculation. The corresponding substitution solution can naturally alsobe infused into a separate venous entry of the patient.

[0063] To carry out the method of the invention, the complexing of theCa/citrate complex is prevented, for example, in that the addition ofcitrate is temporarily interrupted. The Ca concentration increasesaccordingly and the Ca ion concentration on the dialysate side can bemeasured by the Ca sensor visible in FIG. 2. The parameters QD and QBcharacterise the dialysate flow and blood flow respectively. Adetermination of the Ca ion concentration in the patient's blood ispossible in that the dialysate flow is reduced by so much that the Caion concentration on the dialysate side is adapted to the Ca ionconcentration on the blood side. The concentration on the blood side canbe determined without a change to the blood flow and dialysate flowusual in the treatment from the measured concentration on the dialysateside also by means of the known above-mentioned relationships betweenthe entry concentration of the Ca ions on the blood side, the measuredstarting concentration of the Ca ions on the dialysate side, thedialysate flow and the clearance.

[0064]FIG. 3 shows the adaptation of the concentration of an NaClsolution on the dialysate side to the concentration on the blood side ona reduction of the dialysate flow. If the dialysate flow is selected tobe sufficiently low—dependent on the blood flow, the relevant moleculeand the dialyser used—the dialysate concentration practicallycorresponds to the blood concentration. The dialysate then reachessaturation. In this way, the concentration in the blood can bedetermined with good precision from the measured concentration in thedialysate.

[0065]FIG. 4 shows the response function of the Ca ion concentration inthe dialysate with an abrupt interruption of the citrate infusion. Therectangle function shown reproduces the time curve of the citrateinfusion. As can be seen from FIG. 4, the citrate infusion isinterrupted in the time interval t=1 to t=4. The other curve shownreproduces the concentration curve of Ca ions on the dialysate side. Theordinates of both figures and the abscissa have any desired units sinceit is not a question of absolute values here. After the infusion flowhas been switched off (t=1), the low Ca ion concentration will initiallystill remain at the site of the sensor. The reason is that the volume ofthe hose connections acts as a dead volume between the infusion pointand the position of the sensor. Dead times in the range fromapproximately 10 to 30 s are usual. As can further be seen from FIG. 4,the Ca ion concentration on the dialysate side subsequently increases.Due to the mixing of blood and dialysate with a respective high and lowcitrate concentration above all in the dialysate, the increase will notbe sharp, but the concentration will approximate to an equilibriumvalue. The increase is illustrated in a simplified manner as anexponential function in FIG. 4. Usually, time constants fromapproximately 1 to 2 min can be anticipated with this. Then aquasi-stationary state is reached so that the concentration determinedhere can serve with good precision as the measured value. After thecitrate infusion is turned back on (t=4), the dead time first becomeseffective again. Subsequently, the Ca ion concentration falls in orderto finally approximate to the low equilibrium value with an on-goingcitrate infusion.

[0066]FIG. 5 shows a method variant in which the interruption of thecitrate infusion is not necessary. Here, the Ca ion concentration isdetermined in that the Ca ion is again released from the Ca citratecomplex. This takes place by the supply of an acid (see Pos. 4). In thisway, the pH is preferably reduced to a range from 2 to 3, which resultsin a dissociation of the complex and correspondingly releases the Caions. The advantage of this method variant is that no interruption ofanti-coagulation takes place since the citrate addition is notinterrupted.

[0067] The present invention makes it possible to monitor the actualphysiologically relevant and critical parameters of the Ca ionconcentration and the Mg ion concentration of the patient's blood duringthe whole therapy such that it is ensured at every point of thetreatment that a state endangering the health of the patient isprecluded. The pre-requisite is naturally that the determination of theCa ion value and of the Mg ion value takes place reliably. A goodreliability can be achieved here by a redundant sensor embodiment or bysensors which perform self-tests. In addition to the use of sensors,other methods can naturally also be used to determine the ionconcentration.

[0068] Whereas previously known monitoring systems generally only relateto individual technical components such as the monitoring of a pump withseparate or integrated monitoring systems, for example droppers whichallow the monitoring of an infusion, the monitoring of the ionconcentration of the patient in accordance with the invention as theactual physiologically relevant critical parameter includes the wholetherapy and thus takes every partial aspect of the method into account.

1. A method for determining the concentration of an ion, atom ormolecule bound in a complex, characterised in that the complexing of theion, atom or molecule is prevented at least during the determination ofthe concentration by the addition or withdrawal of a substance.
 2. Amethod in accordance with claim 1, wherein the added substance is anacid and the complexing is prevented by a pH change.
 3. A method inaccordance with claim 1, wherein the complexing is prevented in that theaddition of the complexing agent is interrupted or that the complexingagent enters into a complex with another added substance and therebyreleases the ion, atom or molecule whose concentration is to bedetermined.
 4. A method in accordance with any of claims 1 to 3, whereinit is a question of a method for determining the ion concentration ofblood of a patient in haemo-dialysis and/or haemo-filtrationanti-coagulated with citrate, with the ion concentration of the bloodbeing determined on the basis of the determination of the ionconcentration in the dialysate and with the complexing of the relevantion with citrate being prevented before the determination of the ionconcentration in the dialysate for the purpose of determining theconcentration.
 5. A method in accordance with claim 4, wherein thecomplexing is prevented in that the citrate addition into the bloodcirculation is temporarily interrupted.
 6. A method in accordance withclaim 4, wherein the complexing is prevented in that the ion is releasedfrom the ion/citrate complex in the dialysate by lowering the pH.
 7. Amethod in accordance with claim 5, wherein the measurement of the ionconcentration in the dialysate is carried out after interrupting thecitrate addition at the end of a length of time which is composed of adead time caused by dead volumes and of a period of time required toreach a quasi-stationary state.
 8. A method in accordance with claim 5,wherein the measurement of the ion concentration in the dialysate iscarried out a multiple of times after interrupting the citrate additionand the measured value is determined after reaching a quasi-stationarystate.
 9. A method in accordance with claim 5, wherein the measurementof the ion concentration is repeated a multiple of times afterinterrupting the citrate addition and the measured value is determinedby extrapolation of the ion concentrations obtained in the dialysate.10. A method in accordance with claim 5, wherein the citrateconcentration is interrupted for a pre-determined time interval and themeasured value is determined by integration of the area of the responsefunction defined by the ion concentration in the dialysate as a functionof time.
 11. A method in accordance with claim 6, wherein the pH is setto the range pH=2-3.
 12. A method in accordance with either of claims 6or 11, wherein the setting of the pH in the dialysate takes place bymeans of an infusion of acid.
 13. A method in accordance with any ofclaims 4 to 12, wherein the dialysate flow is reduced for the purpose ofapproximating the ion concentration of the dialysate to the ionconcentration of the blood.
 14. A method in accordance with any ofclaims 4 to 13, wherein the determination of the ion concentration ofthe blood takes place by calculation without reducing the dialysateflow.
 15. A method in accordance with any of claims 4 to 14, wherein thedetection of the ion concentration in the dialysate takes place by meansof an ion-sensitive sensor in the dialysate flowing away from thedialyser.
 16. A method in accordance with any of claims 4 to 15, whereinthe determined ion concentration of the blood of a patient serves as acontrolled variable whose value is influenced by the control variablesof citrate addition and/or addition of a substitution medium containingions.
 17. A method in accordance with any of claims 4 to 16, wherein analarm is triggered when the determined ion concentration in the blood ofthe patient lies outside a permitted range or differs from a permittedvalue.
 18. A method in accordance with any of claims 4 to 17, whereinthe ion concentration in the compartment of the dialyser on the bloodside is determined without interrupting the citrate supply and iscompared with a permitted threshold value of the ion concentration andthe citrate feed is changed in dependence on this comparison.
 19. Amethod in accordance with any of claims 4 to 18, wherein the ions arecalcium ions and/or magnesium ions.
 20. A dialyser having ahaemo-dialyser and/or a haemo-filter and having an extra-corporal bloodcirculation with which means for the adding of citrate to the blood areconnected upstream of the haemo-dialyser and/or of the haemo-filter andmeans for the adding of a substitution solution containing ions to theblood are connected downstream of the haemo-dialyser and/or of thehaemo-filter, and having a dialysate line which has means for thedetection of an ion concentration in the dialysate downstream of thehaemo-dialyser and/or of the haemo-filter with respect to the directionof flow of the dialysate.
 21. A dialyser in accordance with claim 20,wherein the means for the detection of the ion concentration aredesigned in the form of one or more ion-sensitive sensors.
 22. Adialyser in accordance with claim 21, wherein a test device is providedwhich performs a function check of the sensor(s) in time intervals or onactuation by an operator.
 23. A dialyser in accordance with any ofclaims 20 to 22, wherein means for adding a substance are connected tothe dialysis line by which the pH of the dialysate can be changed.
 24. Adialyser in accordance with claim 23, wherein the means are disposedsuch that the addition takes place downstream of the dialyser withrespect to the direction of flow.
 25. A dialyser in accordance with anyof claims 20 to 24, wherein means are provided by which the dialysateflow can be reduced temporarily.
 26. A dialyser in accordance with anyof claims 20 to 25, wherein a control unit is provided which controlsthe means for adding citrate to the blood in time intervals or onactuation by the operator such that the addition is temporarilyinterrupted and which records the concentration value determined by themeans for detecting an ion concentration in the dialysate after thestart of the interruption of the citrate addition continuously or intime intervals.
 27. A dialyser in accordance with claim 26, wherein thecontrol unit is designed such that this determines the measured value ofthe Ca⁺⁺ ion concentration in accordance with a method in accordancewith claims 7 to
 10. 28. A dialyser in accordance with any of claims 20to 27, wherein a regulating unit is provided which is connected to themeans for detecting an ion concentration in the dialysate and to themeans for adding citrate and/or to the means for adding a substitutionsolution containing ions and which initiates an increase or a loweringof the addition amount of citrate and/or of substitution solutioncontaining ions in dependence on the comparison between a nominal valueor a nominal value range and the determined actual value of the ionconcentration.
 29. A dialyser in accordance with claim 28, wherein theregulating unit and/or the means for adding citrate are designed suchthat the concentration of citrate cannot be lowered below a thresholdvalue.
 30. A dialyser in accordance with any of claims 20 to 29, whereinan alarm unit is provided which triggers an alarm on determination of acritical individual measurement of the ion concentration or ondetermination of a critical trend of individual measurements.